R01 CA67819, entitled "Clinical Trials of Flavopiridol with Chemotherapy", has been devoted to the clinical development of the cyclin dependent kinase inhibitor flavopiridol in combination with chemotherapy in the treatment of advanced human cancers. This program is based on discoveries made in our laboratory that flavopiridol enhances the induction of apoptosis by a broad range of chemotherapeutic agents. Based on the strength of our laboratory and clinical data, we initiated our R01 supported phase I clinical trial of sequential CPT-11 and flavopiridol with surrogate markers of response, a phase II clinical trial of sequential paclitaxel and flavopiridol in patients with paclitaxel refractory, metastatic esophagus cancer, and further laboratory studies to identify potential surrogate markers for response with the CPT-11 and flavopiridol combination. We have not only achieved these aims but have also considerably exceeded them. In particular, we have completed both of these phase I and II clinical trials, have successfully evaluated a series of molecular markers and correlated them to response, have identified new biomarkers (including drg1), have made considerable laboratory progress in identifying new flavopiridol combinations, and are in the process of translating these laboratory studies into clinical cancer research. Based on our laboratory and clinical results, this grant renewal will represent a focused approached to the continued development of flavopiridol. In particular, we plan to test flavopiridol, as an agent that enhances the effect of CPT-11, and develop flavopiridol with chemotherapy and radiation in the treatment of pancreatic cancer. The specific aims of this R01 grant renewal will be to: 1. Complete the current phase I trials of flavopiridol in combination with CPT-11-based chemotherapy, with continued testing of biomarkers of response. This includes CPT-11 and cisplatin (MSKCC IRB# 02-043/NCI # 5700) and CPT-11 as part of the FOLFIRI regimen (MSKCC IRB # 02-024, NCI #5757). 2. Develop a clinical program of flavopiridol-modulated therapy with radiation (MSKCC IRB # 02-034/NCI # 5764) gemcitabine (MSKCC IRB # pending/NCI # 6051), and docetaxel (NCI LOI#6366) for the treatment of both locally advanced and metastatic pancreas cancer, and 3. Continue to examine the mechanisms by which flavopiridol potentiates CPT-11 induced apoptosis, which should provide the opportunity to identify new biomarkers of response for these flavopiridol drug combinations.